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Potential Drugs (potential + drug)
Terms modified by Potential Drugs Selected AbstractsN-in-1 dosing pharmacokinetics in drug discovery: Experience, theoretical and practical considerationsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2008Kan He Abstract N-in-1 (or cassette) dosing pharmacokinetics (PK) has been used in drug discovery for rapid assessment of PK properties of new chemical entities. However, because of potential for drug,drug interactions this procedure is still controversial. This study was to retrospectively evaluate the N-in-1 dosing approach in drug discovery with an emphasis on the potential for drug,drug interactions. The systemic clearance, volume of distribution, oral bioavailability, and renal excretion of the 31 lead compounds in rats, dogs or chimpanzees were significantly correlated between the N-in-1 dosing and discrete studies with r values of 0.69, 0.91, 0.53, and 0.83 (p,<,0.005 for all), respectively. PK parameters for 11 quality control compounds which were involved in 194 N-in-1 studies for screening approximately 1000 compounds had coefficient of variations of less than 70%. The intrinsic microsomal clearances generated from the N-in-1 and discrete incubations were nearly identical (r,=,0.97, p,<,0.0001). The intrinsic clearances of quality control compound from the N-in-1 incubations were consistent with its discrete CLint estimate (cv: 5.4%). Therefore, N-in-1 dosing is a useful approach in drug discovery to quickly obtain initial PK estimates. Potential drug,drug interactions that result in confounding PK estimates do not occur as frequently as expected. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:2568,2580, 2008 [source] The use of systemic antibiotics in the treatment of chronic woundsDERMATOLOGIC THERAPY, Issue 6 2006Robert Hernandez ABSTRACT:, The role of microorganisms in the etiology and persistence of chronic wounds remains poorly understood. The chronic wound bed houses a complex microenvironment that typically includes more than one bacterial species. Difficulty lies in determining when the presence of bacteria impedes wound healing, thereby warranting intervention. Indications for antibiotic therapy and optimal treatment regimens are ill defined. The goal of this article is to describe the appropriate role of systemic antibiotics in the management of chronic wounds. A common sense approach will be offered based on six clinically pertinent questions: ,,Is infection present? ,,Are systemic antibiotics necessary? ,,Should treatment be enteral or parenteral? ,,What antibiotic or combination of antibiotics should be used? ,,What should be the duration of therapy? ,,What special circumstances are present (i.e., concomitant illnesses, potential drug,drug interactions) that can impact therapy? [source] Modulatory potential of ellagic acid, a natural plant polyphenol on altered lipid profile and lipid peroxidation status during alcohol-induced toxicity: A pathohistological studyJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 2 2008Nagarajan Devipriya Abstract Polyphenol-rich dietary foodstuffs, consumed as an integral part of vegetables, fruits, and beverages have attracted attention due to their antioxidant and anticancer properties. Ellagic acid (EA), a polyphenolic compound widely distributed in fruits and nuts, has been reported to scavenge free radicals and inhibit lipid peroxidation. Chronic consumption of alcohol potentially results in serious illness including hepatitis, fatty liver, hypertriglyceridemia, and cirrhosis. A little is known about the influence of EA on alcohol toxicity in vivo. Accordingly, in the present study, we have evaluated the protective effects of EA on lipid peroxidation and lipid levels during alcohol-induced toxicity in experimental rats. Forty female albino Wistar rats, which were weighing between 150,170 g were used for the study. The toxicity was induced by administration of 20% alcohol orally (7.9 g/kg body wt.) for 45 days. Rats were treated with EA at three different doses (30, 60, and 90 mg/kg body wt.) via intragastric intubations together with alcohol. At the end of experimental duration, liver marker enzymes (i.e., aspartate transaminase, alanine transaminase), lipid peroxidative indices (i.e., thiobarbituriacid reactive substances and hydroperoxides) in plasma, and lipid levels (i.e., cholesterol, free fatty acids, triglycerides and phospholipids) in tissues were analyzed to evaluate the antiperoxidative and antilipidemic effects of EA. Liver marker enzymes, lipid peroxidative indices, and lipid levels, i.e., cholesterol, triglycerides and free fatty acids, were significantly increased whereas phospholipid levels were significantly decreased in the alcohol-administered group. EA treatment resulted in positive modulation of marker enzymes, peroxidative indices, and lipid levels. EA at the dose of 60 mg/kg body wt. was found to be more effective when compared to the other two doses. Histological changes observed were also inconsistent with the biochemical parameters. Our study suggests that EA exerts beneficial effects at the dosage of 60 mg/kg body wt. against alcohol-induced damage, and it can be used as a potential drug for the treatment of alcohol-abuse ailments in the near future. © 2008 Wiley Periodicals, Inc. J Biochem Mol Toxicol 22:101,112, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20226 [source] Clinical drug interactions in outpatients of a university hospital in ThailandJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 6 2005B. Janchawee PhD Summary Background:, A clinical event is likely to occur in patients receiving a pair of drugs, that have the potential to cause an interaction. The occurrence of a clinical drug,drug interaction in outpatients of university hospitals in Thailand is unknown. Purpose:, To investigate the occurrence of a clinical event associated with drug,drug interactions in outpatients at a Thai university hospital. Methods:, A case,control study was established. The case was a sample group, randomly selected from a 1-year sample of outpatient prescriptions containing ,significance-1' potential drug,drug interactions, whereas the control was from the same year but with no potential drug interactions. Medical records of the cases and the controls were reviewed for an adverse event (AE) using a newly developed review form. The odds ratio of occurrence of the AE between the cases and the controls was determined. The AE was assessed for its possibility of being caused from a drug,drug interaction. Results:, The most common specific AE in both the cases and the controls was cough. An unplanned revisit to outpatient department or emergency room was found to be the most common general AE. The odds ratio of the occurrence of an AE in the cases, compared with the controls, was 1·495 (95% CI: 0·917,2·438). The possibility that the AEs resulted from drug interactions in the case group was nine ,probable' patients and 15 ,possible' patients, whereas that in the control group was eight ,possible' patients. The most common interacting drug pair was isoniazid,rifampin with an increase in serum hepatic enzymes as the corresponding AE. Conclusions:, Despite outpatients receiving drug pairs with a high potential for adverse interactions, the rate of occurrence of clinical drug interaction events was low. [source] Pharmacoepidemiologic study of potential drug interactions in outpatients of a university hospital in ThailandJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 1 2005B. Janchawee PhD Summary Background:, Drug,drug interaction is a potential cause of adverse drug reactions. The incidence of such drug interactions in university hospitals in Thailand is unknown. Purpose:, To estimate the rate of potential drug,drug interactions in outpatients of a typical Thai university hospital, and to identify risk factors for such interactions in Thai patients. Methods:, One-year outpatients' prescription data were retrieved from the hospital computer records. Potential drug interactions were identified using the existing drug-interaction database system. Potential interactions within a specific prescription and involving drugs prescribed 1-, 3- and 7-day earlier were searched for. Possible associations between occurrence of an interaction and a patient's age and gender and the number of items on the prescription were explored. Results:, The overall rate of potential drug interactions was 27·9% with a maximal value of 57·8% at the Department of Psychiatry. The rate of the most potentially significant interactions was 2·6%, being the highest in the Department of Medicine (6·0%), with isoniazid vs. rifampin as the most common interacting combination. The rate increased with the patient's age and prescription size (P = 0·000). The odd's ratio of having at least one potential drug interaction was 1·8 (64·2%) when age increased by 20 years (P = 0·000) and 2·8 (165·7%) when another drug was added (P = 0·000). The rate of potential drug interactions was the same for both genders. The rate of potential drug interactions detected across prescriptions was higher than within prescriptions and was dependent on the time interval between prescriptions. Conclusions:, Potential drug interactions were common in our sample of patients. The rate of such interactions increased with the number of drugs prescribed and the patient's age. [source] Effect of Piperine, a Major Component of Black Pepper, on the Intestinal Absorption of Fexofenadine and Its Implication on Food,Drug InteractionJOURNAL OF FOOD SCIENCE, Issue 3 2010Ming-Ji Jin ABSTRACT:, The present study aimed to investigate the effect of piperine, a major component of black pepper, on the oral exposure of fexofenadine in rats. Pharmacokinetic parameters of fexofenadine were determined in rats following an oral (10 mg/kg) or intravenous (5 mg/kg) administration of fexofenadine in the presence and absence of piperine (10 or 20 mg/kg, given orally). Compared to the control group given fexofenadine alone, the combined use of piperine increased the oral exposure (AUC) of fexofenadine by 180% to 190% while there was no significant change in,Cmax and,T1/2 of fexofenadine in rats. The bioavailability of fexofenadine was increased by approximately 2-folds via the concomitant use of piperine. Furthermore,,Tmax tends to be increased which might be attributed to the delayed gastric emptying in the presence of piperine. In contrast, piperine did not alter the intravenous pharmacokinetics of fexofenadine, implying that piperine may increase mainly the gastrointestinal absorption of fexofenadine rather than reducing hepatic extraction. In conclusion, piperine significantly enhanced the oral exposure of fexofenadine in rats likely by the inhibition of P-glycoprotein-mediated cellular efflux during the intestinal absorption, suggesting that the combined use of piperine or piperine-containing diet with fexofenadine may require close monitoring for potential drug,diet interactions. [source] Biomimetic affinity purification of cardiotoxin and its pharmacological effects on the nervous system,JOURNAL OF MOLECULAR RECOGNITION, Issue 3 2008Dexian Dong Abstract Cobra venom is a very precious natural resource. The traditional method for purification of cardiotoxin from cobra venom is a multi-step, high cost, and low recovery procedure. By molecular modeling and docking with SYBYL software, we designed and synthesized an affinity ligand, m-aminobenzoic acid, for high efficiency purification of this therapeutically useful Chinese cobra venom cardiotoxin. The one-step recovery of cardiotoxin reached 64% and the purity reached 92% upon purification. The binding capacity of this synthetic ligand was 9.1,mg cardiotoxin/g moist weight gel and the affinity constant for cardiotoxin was 5.5,×,103,M,1. Unlike a natural affinity ligand, this synthetic ligand is highly stable, and has great potential for industrial scale production of cardiotoxin. In addition, we examined the effects of cardiotoxin on the nervous system in a mouse model. Results showed that cardiotoxin could maintain analgesic effects for 120,min with a dose of less than 0.06,mg/kg (2.8% of the LD50). Administration of 0.12,mg/kg cardiotoxin could improve scopolamine impairments of memory in mice. These results suggest that cardiotoxin may be a potential drug for nervous system diseases. Copyright © 2008 John Wiley & Sons, Ltd. [source] Practical pharmacovigilance analysis strategiesPHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 7 2003A. Lawrence Gould Abstract Purpose To compare two recently proposed Bayesian methods for quantitative pharmacovigilance with respect to assumptions and results, and to describe some practical strategies for their use. Methods The two methods were expressed in common terms to simplify identifying similarities and differences, some extensions to both methods were provided, and the empirical Bayes method was applied to accumulated experience on a new antihypertensive drug to elucidate the pattern of adverse-event reporting. Both methods use the logarithm of the proportional risk ratio as the basic metric for association. Results The two methods provide similar numerical results for frequently reported events, but not necessarily when few events are reported. Using a lower 5% quantile of the posterior distribution gives some assurance that potential signals are unlikely to be noise. The calculations indicated that most potential adverse event,drug associations that were well-recognized after 6 years of use could be identified within the first year, that most of the associations identified in the first year persisted over time. Other insights into the pattern of event reporting were also noted. Conclusion Both methods can provide useful early signals of potential drug,event associations that subsequently can be the focus of detailed evaluation by skilled clinicians and epidemiologists. Copyright © 2002 John Wiley & Sons, Ltd. [source] Modified chitosan III, superabsorbency, salt- and pH-sensitivity of smart ampholytic hydrogels from chitosan-g-PANPOLYMERS FOR ADVANCED TECHNOLOGIES, Issue 4 2004G. R. Mahdavinia Abstract Polyacrylonitrile (PAN) grafted chitosan was prepared by ceric-initiated graft polymerization of acrylonitrile onto chitosan in a homogenous medium. The copolymer chitosan-g-PAN product was then hydrolyzed to yield a novel smart hydrogel (H-chitoPAN) with superabsorbing properties. The influence of add-on values as well as temperature and time of hydrolysis of the initial chitosan-g-PAN on swelling behavior of the hydrogel was evaluated in water and various salt solutions. The swelling kinetics of the superabsorbing hydrogel was studied as well. The hydrogels exhibited ampholytic and pH-sensitivity characteristics. Several sharp swelling changes were observed in lieu of pH variations in a wide range (pH 2,13). The swelling variations were explained according to swelling theory based on the hydrogel chemical structure. Superabsorbency, pH- and salt-sensitivity of the chitosan-based hydrogel was briefly compared with the classical starch-based superabsorbent, H-SPAN. The pH-reversibility and on,off switching behavior of the intelligent H-chitoPAN hydrogels makes them good candidates for considering as potential drug carries. Copyright © 2004 John Wiley & Sons, Ltd. [source] Ef,ciency of antidepressant drugs as monoamine reuptake inhibitors: analysis of the hydrophobicity in,uence using biopartitioning micellar chromatographic dataBIOMEDICAL CHROMATOGRAPHY, Issue 7 2004C. Quiñones-Torrelo Abstract The reuptake blockade of biogenic amines by antidepressants is related not only to their therapeutics effects, but also to their side effects and potential drug,drug interactions. As an alternative to classical quantitative structure,activity relationships studies, in this work we propose different quantitative retention,activity relationships (QRAR) models that are able to describe the monoamine reuptake inhibition by antidepressants. The retention of compounds is measured using a biopartitioning micellar chromatography (BMC) system that can simulate the same hydrophobic, electronic and steric molecular interactions as those that condition drug activity. Since all the compounds considered in this work are structurally related because all of them share the same molecular features as the corresponding basic pharmacophore, the results obtained show that there is a retention range in which antidepressants present the highest monoamine reuptake inhibitor potency. Copyright © 2003 John Wiley & Sons, Ltd. [source] A tethered ascorbate-norepinephrine compound, 4-UT, displays long-acting adrenergic activity on rabbit aortic smooth muscleDRUG DEVELOPMENT RESEARCH, Issue 5 2008Robert Root-Bernstein Abstract We previously demonstrated that adrenergic and histaminergic receptors have an ascorbic acid (vitamin C) binding site on the first extracellular loop, immediately adjacent to the aminergic binding site. Binding of ascorbate to this site strongly potentiates any sub-maximal dose of an adrenergic or histaminergic compound, significantly increasing its duration of activity. We report here the successful synthesis of a tethered compound that mimics the combined effects of a mixture of ascorbate with norepinephrine. The tethered compound uses a four-unit polyethylene linker to tether ascorbate to norepinephrine. The tethered compound is about tenfold less effective than norepinephrine in stimulating rabbit aortic smooth muscle, but has a very significantly enhanced duration of activity compared with norepinephrine alone and comparable to a mixture of norepinephrine and ascorbate. Additional ascorbate does not enhance the tethered compound's effects and we demonstrate that the compound binds to a synthetic peptide spanning the ascorbate binding site of the receptor. These experiments strongly suggest that the compound binds to both the adrenergic binding site and the ascorbate binding site simultaneously. Tethered compounds with linkers of other lengths did not have these properties. We believe that the synthesis of enhanced adrenergic and histaminergic drugs by tethering them to potentiators such as ascorbate will permit a new class of potential drugs to be created with high specificity and long duration of activity. Drug Dev Res 69:242,250, 2008. © 2008 Wiley-Liss, Inc. [source] Combined effect of the finasteride and doxazosin on rat ventral prostate morphology and physiologyINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 3 2010Luis A. Justulin Jr Summary Finasteride (Fin) and Doxazosin (Dox), alone or in combination, have been widely used in treatment of benign prostatic hyperplasia (BPH) symptoms and recently have been suggested as potential drugs for prostate cancer (PCa)prevention and treatment. However, little is known about the effects of the combination therapy on prostate tissue morphology, physiology and matrix metalloproteinases (MMPs) activity, a special set of enzymes closely related to PCa progression and metastasis. In this study, adult Wistar rats were treated with Fin + Dox (25 mg/kg per day) and the ventral prostate (VP) was excised at days 3 and 30 of treatment to evaluate morphology, cell proliferation, death, transforming growth factor-beta1 (TGF-,1) protein expression, MMP-2, MMP-9 activities and MMP-2, MMP-9, TIMP-1 and TIMP-2 mRNA expression. Fin + Dox treatment induced a transient increase in testosterone (T) plasma concentration and a permanent reduction in dihydrotestosterone (DHT). The VP and epithelial cell proliferation were reduced and the stromal collagen fibre volume fraction and apoptosis of the epithelial cell were increased. Fin + Dox treatment also increased the TGF-,1 immunoreaction in the epithelium and in the stroma. The mRNAs for MMP-2, TIMPs-1 and -2 expressions after 30 days of treatment were decreased. The mRNA for MMP-9 was not detected in any of the groups analysed. Fin + Dox treatment for 30 days promoted a decrease in gelatinolytic activity of MMP-2 and an increase in MMP-9. In conclusion, combined treatment with Fin and Dox interferes in the epithelial cell behaviour and in the MMPs activity, potentially via TGF-,1-mediated and androgen pathways. Our results contribute to a better understanding of the clinical data and also of the molecular mechanisms behind isolated or combined Fin and Dox long-term treatment. [source] Amino-terminus domain of the androgen receptor as a molecular target to prevent the hormonal progression of prostate cancerJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2006Gang Wang Abstract Prostate cancer has a propensity to metastasize to the bone. Currently the only effective systemic treatment for these patients is androgen ablation therapy. However, the tumor will invariably progress to an androgen-independent stage and the patient will succumb to his disease within approximately 2 years. The earliest indication of hormonal progression is the rising titer of serum prostate specific antigen. Current evidence implicates the androgen receptor (AR) as a key factor in maintaining the growth of prostate cancer cells in an androgen-depleted state. Under normal conditions, binding of ligand activates the receptor, allowing it to effectively bind to its respective DNA element. However, AR is also transformed in the absence of androgen (ligand-independent activation) in prostate cells via multiple protein kinase pathways and the interleukin-6 (IL-6) pathway that converge upon the N-terminal domain of the AR. This domain is the main region for phosphorylation and is also critical for normal coregulator recruitment. Here we discuss evidence supporting the role of the AR, IL-6 and other protein kinase pathways in the hormonal progression of prostate cancer to androgen independence and the mechanisms involved in activation of the AR by these pathways. Receptor-targeted therapy, especially potential drugs targeting the N-terminal domain, may effectively prevent or delay the hormonal progression of AR-dependent prostate cancer. J. Cell. Biochem. 98: 36,53, 2006. © 2006 Wiley-Liss, Inc. [source] Electrospray ionization mass and tandem mass spectra of a series of N -pyrazolylmethyl and N -triazolylmethyl N -phenylpiperazines: new dopaminergic ligands with potential antipsychotic propertiesJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 6 2005Leonardo S. Santos Abstract Recently, two analogous series of N -pyrazolylmethyl and N -triazolylmethyl N -phenylpiperazines have been prepared and found to be potential antipsychotic drugs acting as new selective ligands of the dopamine D2 receptor. Herein we report a systematic study of their high-resolution electrospray ionization mass and tandem mass spectra in which the main dissociation routes of their protonated molecules are determined and rationalized. The ESI-MS/MS data is very characteristic for both series allowing straightforward isomeric differentiation. A single and dominant fragment ion for the pyrazole series and four major fragment ions for the triazole series are useful for selective reaction MS monitoring of these potential drugs in biological fluids. Copyright © 2005 John Wiley & Sons, Ltd. [source] Identification of a human estrogen receptor ,-derived antiestrogenic peptide that adopts a polyproline II conformationJOURNAL OF PEPTIDE SCIENCE, Issue 7 2009Josef Kapitán Abstract Polyproline II (PPII) helix is an extended secondary structure present in a number of proteins. PPII-containing sequences mediate specific protein,protein interactions with partners containing appropriate cognate domains called PPII-recognizing domains (PRDs) and are involved in the activation of intracellular signaling pathways. Thus, the identification of PPII structures in proteins is of great interest, not only to explore molecular and physiological mechanisms, but also to elaborate new potential drugs. By revisiting X-ray crystal structures of liganded ,-type human estrogen receptor (ER,), we have identified an 11-residue PPII-helical sequence (D321AEPPILYSEY331) in the ligand-binding domain of the receptor. The data recorded by far-ultraviolet circular dichroism (far-UV CD), vibrational Raman optical activity (ROA) and differential scanning calorimetry (DSC) show that the corresponding peptide (Ac-DAEPPILYSEY-NH2) is particularly well structured in PPII, with the same proportion of PPII as observed from X-ray structures (,85%). In addition, studies carried out on ER,-negative Evsa-T breast cancer cells transiently co-transfected with a pcDNA3-ER, plasmid and a Vit-tk-Luc reporter gene revealed that the peptide antagonizes the estradiol-induced transcription providing perspectives for researching new molecules with antagonistic properties. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd. [source] Peptide dynamic fingerprints: a tool for investigating the role of conformational flexibility for GLP-1 analogs affinityJOURNAL OF PEPTIDE SCIENCE, Issue 8 2005Dr M. Adenot Abstract Glucagon-like peptide-1 (GLP-1) is a 30-residue peptide implicated in short-term appetite regulation. Its analogs are presumed to be potential drugs against obesity and non-insulin dependent diabetes mellitus (NIDDM or type 2 diabetes). This study examined how the dynamic fingerprints can be used for establishing dynamics,activity relationships in a series of peptides for which the mechanism of action is unknown and in which mutations can cause an increase or decrease in biological activity. The 3D autocorrelation method was used to generate maps of both active and inactive analogs. As the active conformation of GLP-1 is not yet clearly defined, the dynamic fingerprints of peptides in an aqueous environment were compared to explain the high affinity of the peptide for its receptor. The suggestion that the peptide could bind to the receptor in a folded conformation has been examined. In the case of the GLP-1 analogs, it was shown that the folding tendency cannot be directly related to affinity values and the results do not favor a folded active conformation model of GLP-1. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd. [source] Acetylcholinesterase inhibitors from Stephania venosa tuberJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2006Kornkanok Ingkaninan Acetylcholinesterase (AChE) inhibitors have lately gained interest as potential drugs in the treatment of Alzheimer's disease. Three AChE inhibitors were isolated from tubers of a Thai medicinal plant, Stephania venosa (Bl) Spreng. They were identified as quaternary protoberberine alkaloids, stepharanine, cyclanoline and N -methyl stepholidine. They expressed inhibitory activity on AChE with IC50 values (concentration that caused 50% inhibition of activity) of 14.1K ± 0.81, 9.23 ± 3.47 and 31.30 ± 3.67 ,M, respectively. The AChE inhibitory activity of these compounds was compared with those of the related compounds, palmatine, jatrorrhizine and berberine, as well as tertiary protoberberine alkaloids isolated from the same plant, stepholidine and corydalmine. The results suggest that the positive charge at the nitrogen of the tetrahydroisoquinoline portion, steric substitution at the nitrogen, planarity of the molecule or substitutions at C-2, ,3, ,9, and ,10 affect the AChE inhibitory activity of protoberberine alkaloids. [source] Protective effect of vitamin E on ultraviolet B light,induced damage in keratinocytesMOLECULAR CARCINOGENESIS, Issue 3 2002Samar Maalouf Abstract Ultraviolet (UV) B radiation is the most common environmental factor in the pathogenesis of skin cancer. Exposure of human skin to UVB radiation leads to the depletion of cutaneous antioxidants, the activation of nuclear factor kappa B (NF-,B), and programmed cell death (apoptosis). Although antioxidant supplementation has been shown to prevent UVB-induced photooxidative damage, its effect on components of cell signaling pathways leading to gene expression has not been clearly established. In the present study, the effect of the antioxidant vitamin, ,-tocopherol (,-T), and its acetate analog, ,-tocopherol acetate (,-TAc), on UVB-induced damage in primary and neoplastic mouse keratinocytes was investigated. The ability of both vitamins to modulate UVB-induced apoptosis and activation of the transcription factor NF-,B were studied. Treatment of normal and neoplastic mouse epidermal keratinocytes (308 cells) with 30,60 mJ/cm2 UVB markedly decreased viable cell number and was accompanied by DNA fragmentation. When both vitamins were applied to cells at times before and after UVB radiation, a significant increase in the percentage of viable cells and concomitant decrease in the number of apoptotic cells was noted, with vitamin pretreatment providing a better protection than posttreatment. Simultaneous posttreatment of irradiated cells with ,-TAc abolished the cytotoxic effects of UVB and restored cell viability to control levels. In addition, simultaneous posttreatment of irradiated cells with ,-T reduced the number of apoptotic cells by half, indicating a synergistic effect of two such treatments compared with any single one. Flow cytometry analysis indicated that vitamin treatment suppressed both an increase in pre-G0 cells and a decrease in cycling cells by UVB exposure. In addition, NF-,B activation was detected 2 h after UV exposure and was maintained for up to 8 h. Pretreatment with vitamins significantly inhibited NF-,B activation at 4 and 8 h. These results indicate that vitamin E and its acetate analog can modulate the cellular response to UVB partly through their action on NF-,B activation. Thus, these antioxidant vitamins are potential drugs for the protection from or the reduction of UVB-associated epidermal damage. © 2002 Wiley-Liss, Inc. [source] Clinically relevant drug interactions of current antifungal agentsMYCOSES, Issue 2 2010Paul O. Gubbins Summary Antifungal agents are often prescribed in critically ill patients who are receiving many other medications. When using systemic antifungals, clinicians may possess susceptibility data and they are typically aware of the potential toxicity of these agents. However, the myriad of potential drugs that antifungal agents can interact with is daunting and can be confusing. This article reviews the pharmacokinetic properties of antifungal agents and their clinically relevant drug interactions. The antifungal agents differ markedly in their pharmacokinetic properties and in how they interact with other medicines. The amphotericin B formulations interact with other medicines primarily by reducing their renal elimination or producing additive toxicities. The azoles interact with other medicines primarily by inhibiting biotransformation or by affecting drug distribution and elimination. The echinocandins have the lowest propensity to interact with other medicines. The clinical relevance of antifungal,drug interactions varies substantially. While certain interactions are benign and result in little or no untoward clinical outcomes, others can produce significant toxicity or compromise efficacy if not properly managed through monitoring and dosage adjustment. However, certain interactions produce significant toxicity or compromise efficacy to such an extent that they cannot be managed and the particular combination of antifungal and interacting medicine should be avoided. [source] Cilomilast, tacrolimus and rapamycin modulate dendritic cell function in the elicitation phase of allergic contact dermatitisBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2005W. Bäumer Summary Background, Cilomilast and tacrolimus as well as rapamycin are potential drugs for the treatment of allergic skin diseases like atopic dermatitis and allergic contact dermatitis. Objectives, To compare the in vitro and in vivo immunomodulatory effects of the phosphodiesterase 4 inhibitor cilomilast with those of tacrolimus and rapamycin. Methods, The in vitro action of cilomilast, tacrolimus and rapamycin were tested in a mixed leucocyte reaction (MLR). In vivo, the inhibitory action of the immunomodulatory drugs was compared in the toluene-2,4-diisocyanate (TDI)-induced allergic inflammatory response with particular focus on dendritic cell (DC) function. Results, Cilomilast, tacrolimus and rapamycin were all able to inhibit DC-mediated T-cell activation in a MLR. But it was demonstrated for cilomilast that the target cells are T cells rather than DC. In vivo, a combination of systemic and topical administration of each of these three substances significantly inhibited swelling in the murine ear 16 h after TDI challenge. There was also a reduction in the weight of the draining auricular lymph node, in lymphocyte cell count, and in the number of emigrated DC. The density of Langerhans cells in the epidermis was correspondingly higher in mice treated with cilomilast, tacrolimus and rapamycin than in those treated with vehicle. All three substances were found to inhibit DC migration ex vivo in a skin DC migration assay performed on ear tissue after TDI challenge. Conclusions, DC migration into the draining lymph node also takes place in the elicitation phase of allergic contact dermatitis and this migration can be influenced by tacrolimus and rapamycin, and, to a lesser extent, by cilomilast. [source] Photoactivation of an Inhibitor of the 12/15-Lipoxygenase PathwayCHEMBIOCHEM, Issue 7 2006Stephan Herre Abstract Lipoxygenases are lipid-peroxidizing enzymes that have been implicated in the pathogenesis of inflammatory diseases and lipoxygenase inhibitors may be developed as anti-inflammatory drugs. Structure comparison with known lipoxygenase inhibitors has suggested that (2Z)-2-(3-benzylidene)-3-oxo-2,3-dihydrobenzo[b]thiophene-7-carboxylic acid methyl ester might inhibit the lipoxygenase pathway but we found that it exhibited only a low inhibitory potency for the pure 12/15-lipoxygenase (IC50=0.7 mM). However, photoactivation, which induces a Z -to- E isomerization of the double bond, strongly augmented the inhibitory potency and an IC50 value of 0.021 mM was determined for the pure E isomer. Similar isomer-specific differences were observed with the recombinant enzyme and its 12-lipoxygenating Ile418Ala mutant, as well as in intracellular lipoxygenase activity. Structure modeling of the enzyme/inhibitor complex suggested the molecular reasons for this isomer specificity. Since light-induced isomerization may proceed in the skin, such photoreactive compounds might be developed as potential drugs for inflammatory skin diseases. [source] Research Article: pso@autodock: A Fast Flexible Molecular Docking Program Based on Swarm IntelligenceCHEMICAL BIOLOGY & DRUG DESIGN, Issue 6 2007Vigneshwaran Namasivayam On the quest of novel therapeutics, molecular docking methods have proven to be valuable tools for screening large libraries of compounds determining the interactions of potential drugs with the target proteins. A widely used docking approach is the simulation of the docking process guided by a binding energy function. On the basis of the molecular docking program autodock, we present pso@autodock as a tool for fast flexible molecular docking. Our novel Particle Swarm Optimization (PSO) algorithms varCPSO and varCPSO-ls are suited for rapid docking of highly flexible ligands. Thus, a ligand with 23 rotatable bonds was successfully docked within as few as 100 000 computing steps (rmsd = 0.87 Å), which corresponds to only 10% of the computing time demanded by autodock. In comparison to other docking techniques as gold 3.0, dock 6.0, flexx 2.2.0, autodock 3.05, and sodock, pso@autodock provides the smallest rmsd values for 12 in 37 protein,ligand complexes. The average rmsd value of 1.4 Å is significantly lower then those obtained with the other docking programs, which are all above 2.0 Å. Thus, pso@autodock is suggested as a highly efficient docking program in terms of speed and quality for flexible peptide,protein docking and virtual screening studies. [source] IMMUNOCHEMICAL CHARACTERIZATION OF THE FUNCTIONAL CONSTITUENTS OF TRIPTERYGIUM WILFORDII CONTRIBUTING TO ITS ANTI-INFLAMMATORY PROPERTYCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1 2008Kwong-Fai Wong SUMMARY 1Tripterygium wilfordii (TW) contains bioactive compounds that possess immunosuppressive properties. These compounds are considered to be potential drugs in the treatment of acute graft rejections. However, their structure,activity relationships remain unknown. 2The aim of the present study was to delineate the molecular moieties of triptolide that could account for its ability to inhibit inflammatory responses. In this context, purified TW active compounds (triptolide and triptonide) and synthetic triptolide derivatives were prepared to investigate the structure,activity relationships of triptolide. To this end, rat splenocytes were treated with increasing concentrations of the compounds and then allogenically stimulated using a mixed lymphocyte reaction to determine their antiproliferative activities. From the results, the IC50 value of each compound was calculated. 3Modification of the ,-hydroxyl group at the C-14 position of the triptolide molecule significantly affected the immunosuppressive activity of T59, as demonstrated by a sevenfold increase of the IC50. Conversely, reduction of the ,-butyrolactone group in T60 and T61 completely abrogated the antiproliferative effect. Alterations in the C-14 ,-hydroxyl and ,-butyrolactone groups also resulted in reduced cytotoxicity. 4The present findings demonstrate that the C-14 ,-hydroxyl and ,-butyrolactone moieties of the triptolide molecule are crucial for its anti-inflammatory properties and cytotoxicity and are responsible for the compound's antiproliferative activity. [source] | ||||||||||||||||||||||||||||